Substituted benzimidazoles, processes for their preparation, their use as medicaments, and medicaments comprising them

ABSTRACT

The invention relates to the use of compounds of formula I for the production of a medicament for the treatment of illnesses which can be influenced by inhibition of the Na+/H+ exchanger, and to a medicament comprising them.  
                 
 
     in which R1 to R9 have the meanings shown in the claims.

[0001] This application claims the benefit of the filing date of GermanPatent Application Number 10060292.4, filed on Dec. 5, 2000, whichapplication is hereby incorporated by reference.

[0002] The invention relates to substituted benzimidazoles of formula I

[0003] in which:

[0004] R1 and R5 are, independently of one another, F, Cl, Br, I, CN,alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted orpartially or completely substituted by fluorine; or

[0005] R1 and R5 are cycloalkyl having 3 to 7 carbon atoms, which isunsubstituted or partially or completely substituted by fluorine; or

[0006] R1 and R5 are, independently of one another, OH or O-alkyl having1 to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine; or

[0007] R1 and R5 are, independently of one another, OCOR10, NR11R12,COR13, COOH, COOR14, CONR11 R12, or —(O)_(n)—SO_(m)R15, in which n is 0or 1 and m is 0, 1, or 2; or

[0008] R1 and R5 are O-phenyl, in which phenyl is unsubstituted orsubstituted by one to three substituents selected, independently of oneanother, from F, Cl, Br, I, alkyl having 1 to 4 carbon atoms, OH,O-alkyl having 1 to 4 carbon atoms, NR16R17, CN, or(C₁-C₄)-alkylsulfonyl, in which the alkyl groups are unsubstituted orpartially or completely substituted by fluorine;

[0009] R16 and R17 are, independently of one another, H or alkyl having1 to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine;

[0010] R10 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine;

[0011] R11 and R12 are, independently of one another, H or alkyl having1 to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine, and at least one CH₂ group of saidalkyl is optionally replaced by O or NR18; or

[0012] R11 and R12, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring; or

[0013] R11 and R12 are, independently of one another, COR19 or SO₂R20;

[0014] R18, R19, and R20 are, independently of one another, H or alkylhaving 1 to 4 carbon atoms, in which alkyl is unsubstituted or partiallyor completely substituted by fluorine;

[0015] R13 and R14 are alkyl having 1 to 4 carbon atoms, which isunsubstituted or partially or completely substituted by fluorine;

[0016] R15 is alkyl or O-alkyl, in which the alkyl groups have 1 to 4carbon atoms and are unsubstituted or partially or completelysubstituted by fluorine; or

[0017] R15 is OH or NR21R22;

[0018] R21 and R22 are, independently of one another, H or alkyl having1 to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine, and at least one CH₂ group of saidalkyl is optionally replaced by O or NR23;

[0019] R23 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine; or

[0020] R21 and R22, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring;

[0021] but R1 and R5 cannot simultaneously be Cl or CH₃;

[0022] R2, R3, and R4 are H or one of the radicals R2, R3, or R4 isoptionally F;

[0023] R6, R7, R8, and R9 are, independently of one another, H, F, Cl,Br, I, CN, alkyl, or O-alkyl, in which the alkyl groups have 1 to 4carbon atoms and are unsubstituted or partially or completelysubstituted by fluorine; or

[0024] R6, R7, R8, and R9 are cycloalkyl having 3 to 7 carbon atoms,which is unsubstituted or partially or completely substituted byfluorine; or

[0025] R6, R7, R8, and R9 are, independently of one another, OH, OCOR24,or NR25R26;

[0026] R24 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine;

[0027] R25 and R26 are, independently of one another, H or alkyl having1 to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine; or

[0028] R25 and R26 are COR27; or

[0029] R25 and R26, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring, and at least one CH₂ groupthereof is optionally replaced by O or NR18;

[0030] R27 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine; or

[0031] a pharmaceutically tolerable salt or trifluoroacetate thereof.

[0032] Other embodiments of compounds of formula I are those in which:

[0033] R1 and R5 are, independently of one another, F, Cl, Br, CN, alkylhaving 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, cycloalkyl having 3 to7 carbon atoms, O-alkyl having 1 to 4 carbon atoms, OH, OCF₃, OCH₂CF₃,OCF₂CF₃, OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, —O_(m)—SO₂R15,or O-phenyl;

[0034] m is 0 or 1;

[0035] R10 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, orCF₂CF₃;

[0036] R11 and R12 are, independently of one another, H, alkyl having 1to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, and at least one CH₂ group ofsaid alkyl is optionally replaced by O or NR18; or

[0037] R11 and R12, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring; or

[0038] R11 and R12 are, independently of one another, COR19 or SO₂R20;

[0039] R18, R19, and R20 are, independently of one another, H, alkylhaving 1 to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;

[0040] R13 and R14 are, independently of one another, alkyl having 1 to4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;

[0041] R15 is alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, OH,O-alkyl having 1 to 4 carbon atoms, OCF₃, OCH₂CF₃, OCF₂CF₃, or NR21 R22;

[0042] R21 and R22 are, independently of one another, H, alkyl having 1to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃; or

[0043] R21 and R22, together with the nitrogen atom to which they arebonded, are —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₂—O—(CH₂)₂—, or 13(CH₂)₂—N—R30-(CH₂)₂;

[0044] R30 is H, CH₃, or CF₃;

[0045] but R1 and R5 cannot simultaneously be Cl or CH₃;

[0046] R2, R3, and R4 are H or one of the radicals R2, R3, or R4 isoptionally F;

[0047] R6, R7, R8, and R9 are, independently of one another, H, F, Cl,Br, I, CN, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃,cycloalkyl having 3 to 7 carbon atoms, OH, O-alkyl having 1 to 4 carbonatoms, OCF₃, OCH₂CF₃, OCF₂CF₃, OCOR24, or NR25R26;

[0048] R24 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, orCF₂CF₃;

[0049] R25 and R26 are, independently of one another, H, alkyl having 1to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, or COR27; or

[0050] R25 and R26, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring;

[0051] R27 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, orCF₂CF₃; or

[0052] a pharmaceutically tolerable salt or trifluoroacetate thereof.

[0053] Another embodiment of compounds of formula I are those in which:

[0054] R1 and R5 are, independently of one another, F, Cl, Br, CN,methyl, ethyl, isopropyl, CF₃, cyclopropyl, OH, O-methyl, O-ethyl,O-isopropyl, OCF₃, O-acetyl, NH₂, N(CH₃)₂, N(CH₂CH₃)₂, N-pyrrolidino,N-piperidino, N-morpholino, N-(N′-methyl)-piperazino, NHSO₂Me, acetyl,COOH, COOR14, CONR11R12, SO₂R15, or O-phenyl;

[0055] R11 and R12 are, independently of one another, H, methyl, orethyl;

[0056] R14 is methyl or ethyl;

[0057] R15 is CH₃, CF₃, OH, OCH₃, OCF₃, or NR21R22;

[0058] R21 and R22 are, independently of one another, H or methyl;

[0059] but R1 and R5 cannot simultaneously be Cl or CH₃;

[0060] R2, R3, and R4 are H;

[0061] R6, R7, R8, and R9 are, independently of one another, H, F, Cl,CN, CH₃, C₂H₅, isopropyl, CF₃, cyclopropyl, OH, OCH₃, OCF₃, O-acetyl, orNR25R26;

[0062] R25 and R26 are, independently of one another, H, methyl, oracetyl; or

[0063] a pharmaceutically tolerable salt or trifluoroacetate thereof.

[0064] Another embodiment of compounds of formula I are those in which:

[0065] R1 and R5 are, independently of one another, F, Cl, Br, CN,methyl, ethyl, isopropyl, CF₃, cyclopropyl, OH, O-methyl, O-ethyl,O-isopropyl, OCF₃, O-acetyl, NH₂, N(CH₃)₂, N(CH₂CH₃)₂, N-pyrrolidino,N-piperidino, N-morpholino, N-(N′-methyl)-piperazino, NHSO₂Me, acetyl,COOH, COOR14, CONR11R12, SO₂R15, or O-phenyl;

[0066] R11 and R12 are, independently of one another, H, methyl, orethyl;

[0067] R14 is methyl or ethyl;

[0068] R15 is CH₃, CF₃, OH, OCH₃, OCF₃, or NR21R22;

[0069] R21 and R22 are, independently of one another, H or methyl;

[0070] but R1 and R5 cannot simultaneously be Cl or CH₃;

[0071] R2, R3, and R4 are H;

[0072] R6 and R9 are, independently of one another, H, F, Cl, CN, CH₃,CF₃, cyclopropyl, OH, OCH₃, OCF₃, O-acetyl, or NR25R26;

[0073] R25 and R26 are, independently of one another, H, methyl, oracetyl;

[0074] R7 and R8 are, independently of one another, H, F, or OH; or

[0075] a pharmaceutically tolerable salt or trifluoroacetate thereof.

[0076] Examples of compounds of formula I are:

[0077] (1H-benzimidazol-2-yl)-(2,6-dichlorophenyl)amine;

[0078] 2-(2,6-dichlorophenylamino)-1H-benzimidazol-4-ol;

[0079] (1H-benzimidazol-2-yl)-(2,6-dimethylphenyl)amine;

[0080] (1H-benzimidazol-2-yl)-(2-chloro-6-methylphenyl)amine;

[0081] (2,6-dichlorophenyl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine;

[0082] (2,6-dichlorophenyl)-(4-methyl-1H-benzimidazol-2-yl )amine;

[0083] (1H-benzimidazol-2-yl)-(2-chloro-6-fluorophenyl)amine;

[0084] (1H-benzimidazol-2-yl)-(2,6-dibromophenyl)amine;

[0085] 2-(2,6-dichlorophenylamino)-5-fluorobenzimidazole;

[0086] 2-(2,6-dichlorophenylamino)-4-fluorobenzimidazole;

[0087] 2-(2-trifluoromethyl-6-chlorophenylamino)benzimidazole;

[0088] 2-(2,6-dichlorophenylamino)-4,5-difluorobenzimidazole;

[0089] 2-(2,6-dichlorophenylamino)-5-hydroxybenzimidazole;

[0090] 2-(2,6-dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazole;

[0091] 2-(2,6-dichlorophenylamino)-4,6-difluorobenzimidazole;

[0092] (1H-benzimidazol-2-yl)-(2-chlorophenyl)amine;

[0093] (1H-benzimidazol-2-yl)-(2-trifluoromethylphenyl)amine;

[0094] (1H-benzimidazol-2-yl)-(2-bromophenyl)amine; and

[0095] (1H-benzimidazol-2-yl)-o-tolylamine; or

[0096] a pharmaceutically tolerable salt or trifluoroacetate thereof.

[0097] In addition, the invention comprises the use of substitutedbenzimidazoles of formula I for the production of a medicament for thetreatment of diseases which are influenced by the NHE3 exchangeinhibitor, in which:

[0098] R1 and R5 are, independently of one another, H, F, Cl, Br, I, CN,alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted orpartially or completely substituted by fluorine; or

[0099] R1 and R5 are cycloalkyl having 3 to 7 carbon atoms, which isunsubstituted or partially or completely substituted by fluorine; or

[0100] R1 and R5 are OH or O-alkyl having 1 to 4 carbon atoms, in whichalkyl is unsubstituted or partially or completely substituted byfluorine; or

[0101] R1 and R5 are OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, or—(O)_(n)—SO_(m)R15, in which n is 0 or 1 and m is 0, 1, or 2; or

[0102] R1 and R5 are O-phenyl, in which phenyl is unsubstituted orsubstituted by one to three substituents selected from F, Cl, Br, I,alkyl having 1 to 4 carbon atoms, OH, O-alkyl having 1 to 4 carbonatoms, NR16R17, CN, or (C₁-C₄)-alkylsulfonyl, in which the alkyl groupsare unsubstituted or partially or completely substituted by fluorine;

[0103] R16 and R17 are H or alkyl having 1 to 4 carbon atoms, in whichalkyl is unsubstituted or partially or completely substituted byfluorine;

[0104] R10 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine;

[0105] R11 and R12 are, independently of one another, H or alkyl having1 to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine, and at least one CH₂ group of saidalkyl is optionally replaced by O or NR18; or

[0106] R11 and R12, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring; or

[0107] R11 and R12 are COR19 or SO₂R20;

[0108] R18, R19, and R20 are, independently of one another, H or alkylhaving 1 to 4 carbon atoms, in which alkyl is unsubstituted or partiallyor completely substituted by fluorine;

[0109] R13 and R14 are alkyl having 1 to 4 carbon atoms, which isunsubstituted or partially or completely substituted by fluorine;

[0110] R15 is alkyl or O-alkyl, in which the alkyl groups have 1 to 4carbon atoms and are unsubstituted or partially or completelysubstituted by fluorine; or

[0111] R15 is OH or NR21R22;

[0112] R21 and R22 are, independently of one another, H or alkyl having1 to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine, and at least one CH₂ group of saidalkyl is optionally replaced by O— or NR23;

[0113] R23 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine; or

[0114] R21 and R22, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring;

[0115] R2, R3, and R4 are, independently of one another, H or F;

[0116] R6, R7, R8, and R9 are, independently of one another, H, F, Cl,Br, I, CN, alkyl, or O-alkyl, in which the alkyl groups have 1 to 4carbon atoms and are unsubstituted or partially or completelysubstituted by fluorine; or

[0117] R6, R7, R8, and R9 are cycloalkyl having 3 to 7 carbon atoms,which is unsubstituted or partially or completely substituted byfluorine; or

[0118] R6, R7, R8, and R9 are OH, OCOR24, or NR25R26;

[0119] R24 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine;

[0120] R25 and R26 are, independently of one another, H or alkyl having1 to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine; or

[0121] R25 and R26 are COR27; or

[0122] R25 and R26, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring, and at least one CH₂ groupthereof is optionally replaced by O or NR18;

[0123] R27 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine; or

[0124] a pharmaceutically tolerable salt thereof.

[0125] Other embodiments comprise the use of compounds of formula I inwhich:

[0126] R1 and R5 are, independently of one another, H, F, Cl, Br, CN,alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, cycloalkyl having3 to 7 carbon atoms, O-alkyl having 1 to 4 carbon atoms, OH, OCF₃,OCH₂CF₃, OCF₂CF₃, OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12,—O_(m)—SO₂R15, or O-phenyl;

[0127] m is 0 or 1;

[0128] R10 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, orCF₂CF₃;

[0129] R11 and R12 are, independently of one another, H, alkyl having 1to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, and at least one CH₂ group ofsaid alkyl is optionally replaced by O or NR18; or

[0130] R11 and R12, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring; or

[0131] R11 and R12 are COR19 or SO₂R20;

[0132] R18, R19, and R20 are, independently of one another, H or alkylhaving 1 to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;

[0133] R13 and R14 are alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, orCF₂CF₃;

[0134] R15 is alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, OH,O-alkyl having 1 to 4 carbon atoms, OCF₃, OCH₂CF₃, OCF₂CF₃, or NR21R22;

[0135] R21 and R22 are, independently of one another, H, alkyl having 1to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃; or

[0136] R21 and R22, together with the nitrogen atom to which they arebonded, are —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₂—O—(CH₂)₂—, or—(CH₂)₂—N—R30-(CH₂)₂;

[0137] R30 is H, CH₃, or CF₃;

[0138] but R1 and R5 cannot simultaneously be Cl or CH₃, and at most oneof the substituents R1 and R5 is hydrogen;

[0139] R2, R3, and R4 are, independently of one another, H or F;

[0140] R6, R7, R8, and R9 are, independently of one another, H, F, Cl,Br, I, CN, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃,cycloalkyl having 3 to 7 carbon atoms, OH, O-alkyl having 1 to 4 carbonatoms, OCF₃, OCH₂CF₃, OCF₂CF₃, OCOR24, or NR25R26;

[0141] R24 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, orCF₂CF₃;

[0142] R25 and R26 are, independently of one another, H, alkyl having 1to4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, or COR27; or

[0143] R25 and R26, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring;

[0144] R27 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, orCF₂CF₃; or

[0145] a pharmaceutically tolerable salt thereof.

[0146] Other embodiments comprise the use of compounds of formula I inwhich:

[0147] R1 and R5 are, independently of one another, H, F, Cl, Br, CN,methyl, ethyl, isopropyl, CF₃, cyclopropyl, OH, O-methyl, O-ethyl,O-isopropyl, OCF₃, O-acetyl, NH₂, N(CH₃)₂, N(CH₂CH₃)₂, N-pyrrolidino,N-piperidino, N-morpholino, N-(N′-methyl)-piperazino, NHSO₂Me, acetyl,COOH, COOR14, CONR11R12, SO₂R15, or O-phenyl;

[0148] R11 and R12 are, independently of one another, H, methyl, orethyl;

[0149] R14 is methyl or ethyl;

[0150] R15 is CH₃, CF₃, OH, OCH₃, OCF₃, or NR21R22;

[0151] R21 and R22 are, independently of one another, H or methyl;

[0152] but R1 and R5 cannot simultaneously be Cl or CH₃, and at most oneof the substituents R1 and R5 is hydrogen;

[0153] R2, R3, and R4 are H;

[0154] R6, R7, R8, and R9 are, independently of one another, H, F, Cl,CN, CH₃, C₂H₅, isopropyl, CF₃, cyclopropyl, OH, OCH₃, OCF₃, O-acetyl, orNR25R26;

[0155] R25 and R26 are, independently of one another, H, methyl, oracetyl; or

[0156] a pharmaceutically tolerable salt thereof.

[0157] Another embodiment comprises the use of compounds of formula I inwhich:

[0158] R1 and R5 are, independently of one another, F, Cl, Br, CN,methyl, ethyl, isopropyl, CF₃, cyclopropyl, OH, O-methyl, O-ethyl,O-isopropyl, OCF₃, O-acetyl, NH₂, N(CH₃)₂, N(CH₂CH₃)₂, N-pyrrolidino,N-piperidino, N-morpholino, N-(N′-methyl)-piperazino, NHSO₂Me, acetyl,COOH, COOR14,CONR11R12, SO₂R15, or O-phenyl;

[0159] R11 and R12 are, independently of one another, H, methyl, orethyl;

[0160] R14 is methyl or ethyl;

[0161] R15 is CH₃, CF₃, OH, OCH₃, OCF₃, or NR21R22;

[0162] R21 and R22 are, independently of one another, H or methyl;

[0163] but R1 and R5 cannot simultaneously be Cl or CH₃, and at most oneof the substituents R1 and R5 is hydrogen;

[0164] R2, R3, and R4 are H;

[0165] R6 and R9 are, independently of one another, H, F, Cl, CN, CH₃,CF₃, cyclopropyl, OH, OCH₃, OCF₃, O-acetyl, or NR25R26;

[0166] R25 and R26 are, independently of one another, H, methyl, oracetyl;

[0167] R7 and R8 are, independently of one another, H, F, or OH; or

[0168] a pharmaceutically tolerable salt thereof.

[0169] Examples comprising the use of compounds of formula I are:

[0170] 1: (1H-benzimidazol-2-yl)-(2,6-dichlorophenyl)amine;

[0171] 2: 2-(2,6-dichlorophenylamino)-1H-benzimidazol-4-ol;

[0172] 3: (1H-benzimidazol-2-yl)-(2,6-dimethylphenyl)amine;

[0173] 4: (1H-benzimidazol-2-yl)-(2-chloro-6-methylphenyl)amine;

[0174] 5: (2,6-dichlorophenyl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine;

[0175] 6: (2,6-dichlorophenyl)-(4-methyl-1H-benzimidazol-2-yl)amine;

[0176] 7: (1H-benzimidazol-2-yl)-(2-chloro-6-fluorophenyl)amine;

[0177] 8: (1H-benzimidazol-2-yl)-(2,6-dibromophenyl)amine;

[0178] 9: 2-(2,6-dichlorophenylamino)-5-fluorobenzimidazole;

[0179] 10: 2-(2,6-dichlorophenylamino)-4-fluorobenzimidazole;

[0180] 11: 2-(2-trifluoromethyl-6-chlorophenylamino)benzimidazole;

[0181] 12: 2-(2,6-dichlorophenylamino)-4,5-difluorobenzimidazole;

[0182] 13: 2-(2,6-dichlorophenylamino)-5 hydroxybenzimidazole;

[0183] 14: 2-(2,6-dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazole;

[0184] 15: 2-(2,6-dichlorophenylamino)-4,6-difluorobenzimidazole;

[0185] 16: (1H-benzimidazol-2-yl)-(2-chlorophenyl)amine;

[0186] 17: (1H-benzimidazol-2-yl)-(2-trifluoromethylphenyl)amine;

[0187] 18: (1H-benzimidazol-2-yl)-(2-bromophenyl)amine; and

[0188] 19: (1H-benzimidazol-2-yl)-o-tolylamine; or

[0189] a pharmaceutically tolerable salt thereof.

[0190] If compounds of formula I contain one or more centers ofasymmetry, these can have either the S or the R configuration. Thecompounds can be present as optical isomers, as diastereomers, asracemates, or as mixtures thereof.

[0191] Compounds of formula I can furthermore be present as tautomers oras a mixture of tautomeric structures. In the case of substitution onthe corresponding N atoms of the benzimidazole structure, the compoundscan be present in the form of the various double bond isomers or as amixture of the double bond isomers.

[0192] The designated alkyl radicals or partially or completelyfluorinated alkyl radicals can be either straight-chain or branched.

[0193] CH₂ units are also the terminal CH₃ groups in an alkyl chain,which are interpreted in this connection as CH₂—H groups.

[0194] The expression “5-, 6-, or 7-membered ring” represents a5-membered to 7-membered heterocyclic ring comprising at least one alkylor heteroatom. Examples of heteroatoms are nitrogen, oxygen, and sulfur.If multiple heteroatoms are contained, these can be identical ordifferent.

[0195] Methods for the preparation of the compounds used are alsodescribed. Thus, compounds of formula I can be prepared in the mannerknown to the person skilled in the art from the underlyingisothiocyanates of formula II and the corresponding phenylenediamines offormula III.

[0196] The thiourea intermediately formed here is cyclized to thecorresponding compounds of formula I by means of mercury(II) oxide (J.Med. Chem., 18, 90-99 (1975)), methyl iodide (Synthesis, 41-42 (1974)),or carbodiimide (Synthesis, 864-865 (1977)). The isothiocyanates offormula II used here, if not commercially obtainable, can be prepared inthe manner known from the literature from the corresponding anilines bythe methods known to the person skilled in the art, e.g., by treatingwith thiophosgene (J. Med. Chem., 18, 90-99 (1975))orthiocarbonyldiimidazole (Justus Liebigs Ann. Chem., 657 (1962)).

[0197] Likewise, starting from the anilines, by treating with NaOH,carbon disulphide, and methyl iodide in processes which are alreadyknown from the literature, it is possible to prepare the correspondingN-aryldithiocarbamates (Synthesis, 961 (1981)) and, from these in turn,the N-aryldithiocarboximidates of formula IV (Synthesis, 375 (1983)),which can be reacted in the presence of the phenylenediamines of formulaIII at elevated temperatures to give the desired compounds of formula I.

[0198] Finally, compounds of formula I can be prepared starting from theanilines and the corresponding 2-substituted benzimidazoles of formula Vby heating.

[0199] X in this case is a leaving group, such as, for example, Cl, Br,or SO₃H (J. Org. Chem., 51, 1882 (1986)).

[0200] British patent specification 1 171 904 describes a generalformula which would even allow o,o-disubstitution in the aniline moiety.However, there is no indication of compounds of formula I actually takeninto consideration which have an o,o-disubstitution pattern, let alonean experimental description. The compounds described in this Britishpatent specification 1 174 904 are protected therein as substanceshaving antibacterial activity. In the case of compounds according to theinvention, it was not possible with the aid of an exemplary compound todetect any antibacterial action, such that the substance class accordingto British patent specification 1 171 904 can be differentiated clearlyfrom the compounds according to the invention, both structurally and inits pharmacological properties.

[0201] Furthermore, some of the benzimidazoles according to theinvention could be constructed from WO 9808818, which are describedtherein as phospholipase inhibitors. However, no single representativeof this class of compound is described therein, neither experimentallynor pharmacologically.

[0202] It was possible to show that compounds of formula I areoutstanding inhibitors of the sodium-hydrogen exchanger (NHE)—inparticular, of the sodium-hydrogen exchanger of subtype 3 (NHE3).

[0203] On account of these properties, the compounds are suitable forthe treatment of diseases which are caused by oxygen deficiency. As aresult of their pharmacological properties, the compounds areoutstandingly suitable as antiarrhythmic medicaments having acardioprotective component for infarct prophylaxis and infarct treatmentand for the treatment of angina pectoris, which also preventivelyinhibit or greatly decrease the pathophysiological processes in theformation of ischemically induced damage, in particular, in thetriggering of ischemically induced cardiac arrhythmias. Because of theirprotective actions against pathological hypoxic and ischemic situations,compounds of formula I can be used, as a result of the inhibition of thecellular Na+/H+ exchange mechanism, as medicaments for the treatment ofall acute or chronic damage caused by ischemia or diseases inducedprimarily or secondarily thereby. This relates to their use asmedicaments for surgical interventions, e.g., in organ transplants,where the compounds can be used both for the protection of the organs inthe donor before and during removal, for the protection of removedorgans, for example, during treatment with or storage thereof inphysiological fluids, and during surgical transfer to the recipient'sbody. The compounds are likewise valuable, protectively actingmedicaments when carrying out angioplastic surgical interventions, forexample, on the heart and on peripheral vessels. Corresponding to theirprotective action against ischemically induced damage, the compounds arealso suitable as medicaments for the treatment of ischemias of thenervous system, in particular, of the CNS, where they are suitable, forexample, for the treatment of stroke or of cerebral edema. Moreover,compounds of formula I used according to the invention are likewisesuitable for the treatment of forms of shock, such as, for example, ofallergic, cardiogenic, hypovolemic, and of bacterial shock.

[0204] Furthermore, the compounds induce an improvement in therespiratory drive and are therefore used for the treatment ofrespiratory conditions in the following clinical conditions anddiseases: disturbed central respiratory drive (e.g., central sleepapneas, sudden infant death, postoperative hypoxia), muscular-relatedrespiratory disorders, respiratory disorders after long-termrespiration, respiratory disorders during adaptation in a highmountainous area, obstructive and mixed forms of sleep apnea, and acuteand chronic lung diseases with hypoxia and hypercapnia.

[0205] The compounds additionally increase the muscle tone of the upperairways such that snoring is suppressed.

[0206] A combination of an NHE inhibitor with a carboanhydrase inhibitor(e.g., acetazol-amide), where the latter produces a metabolic acidosisand thereby even increases the respiratory activity, proves advantageousdue to increased action and decreased use of active substance.

[0207] It has been shown that compounds used according to the inventionhave a mild laxative action and accordingly can be used advantageouslyas laxatives or in the case of threatening intestinal blockage, wherethe prevention of ischemic damage accompanying blockages in theintestinal area is particularly advantageous.

[0208] The possibility furthermore exists of preventing gallstoneformation.

[0209] Moreover, compounds of formula I used according to the inventionare distinguished by strong inhibitory action on the proliferation ofcells, for example, fibroblast cell proliferation and the proliferationof the vascular smooth muscle cells. Therefore, compounds of formula Iare suitable as valuable therapeutics for diseases in which cellproliferation is a primary or secondary cause, and can therefore be usedas antiatherosclerotic agents against diabetic late complications,cancers, fibrotic diseases such as pulmonary fibrosis, fibrosis of theliver or fibrosis of the kidneys, and organ hypertrophies andhyperplasias, in particular, in prostate hyperplasia or prostatehypertrophy.

[0210] Compounds used according to the invention are effectiveinhibitors of the cellular sodium-proton antiporter (Na/H exchanger),which is raised in numerous diseases (e.g., essential hypertension,atherosclerosis, diabetes), even in those cells which are accessible tomeasurements, such as, for example, in erythrocytes, platelets, orleukocytes. Compounds used according to the invention are thereforesuitable as outstanding and simple scientific tools, for example, intheir use as diagnostics for the determination and differentiation ofcertain forms of hypertension, but also of atherosclerosis, diabetes,and proliferative diseases. Moreover, compounds of formula I aresuitable for preventive therapy for the prevention of the genesis ofhigh blood pressure, for example, of essential hypertension.

[0211] It has additionally been found that NHE inhibitors exhibit afavorable influence on the serum lipoproteins. It is generallyrecognized that for the formation of arteriosclerotic vascular changes,in particular, of a heart disease, excessively high blood lipid levels,‘hyperlipoproteinemia’ is a significant risk factor. For the prophylaxisand the regression of atherosclerotic changes, the lowering of raisedserum lipoproteins therefore assumes extreme importance. Compounds usedaccording to the invention can therefore be used for the prophylaxis andfor the regression of atherosclerotic changes, by excluding a causalrisk factor. With this protection of the vessels against the syndrome ofendothelial dysfunction, compounds of formula I are valuable medicamentsfor the prevention and for the treatment of coronary vasospasms,atherogenesis, and atherosclerosis, left-ventricular hypertrophy anddilated cardiomyopathy, and thrombolytic diseases.

[0212] The compounds mentioned are therefore advantageously used for theproduction of a medicament for the prevention and treatment of sleepapneas and muscle-related respiratory disorders; for the production of amedicament for the prevention and treatment of snoring; for theproduction of a medicament for lowering blood pressure; for theproduction of a medicament for the prevention and treatment of diseaseswhich are induced by ischemia and reperfusion of central and peripheralorgans, such as, for example, acute kidney failure, stroke, endogenousstates of shock, and intestinal diseases; for the production of amedicament for the treatment of diabetic late damage and chronic kidneydiseases, in particular, of all kidney inflammations (nephritides) whichare associated with increased protein/albumin excretion; for theproduction of a medicament for the treatment of attack by ectoparasitesin human and veterinary medicine; for the production of a medicament forthe treatment of the diseases mentioned in combination with bloodpressure-lowering substances, typically with angiotensin-convertingenzyme (ACE) inhibitors, with diuretics and saluretics such asfurosemide, hydrochlorothiazide, pseudoaldosterone antagonists, andaldosterone antagonists, and with angiotensin receptor antagonists.

[0213] The administration of sodium-proton exchange inhibitors offormula I as novel medicaments for the lowering of raised blood lipidlevels is claimed, and the combination of sodium-proton exchangeinhibitors with medicaments having blood pressure-lowering and/orhypolipidemic action.

[0214] Typically, the compounds mentioned are advantageously used forthe production of a medicament for the prevention and treatment of sleepapneas and muscle-related respiratory disorders; for the production of amedicament for the prevention and treatment of snoring; for theproduction of a medicament for lowering blood pressure; for theproduction of a medicament for the prevention and treatment of diseaseswhich are induced by ischemia and reperfusion of central and peripheralorgans, such as, for example, acute kidney failure and intestinaldiseases; for the production of a medicament for the treatment ofdiabetic late damage and chronic kidney diseases, in particular, of allkidney inflammations (nephritides) which are associated with increasedprotein/albumin excretion; for the production of a medicament for thetreatment of attack by ectoparasites in human and veterinary medicine;for the production of a medicament for the treatment of the diseasesmentioned in combination with blood pressure-lowering substances,preferably with angiotensin-converting enzyme (ACE) inhibitors, withdiuretics and saluretics such as furosemide, hydrochlorothiazide,pseudoaldosterone antagonists, and aldosterone antagonists, withadenosine receptor modulators, in particular, with adenosine receptoractivators (A2 agonists), and with angiotensin receptor antagonists.

[0215] Pharmaceuticals which contain a compound of formula I can in thiscase be administered orally, parenterally, intravenously, rectally,transdermally, or by inhalation, the administration being dependent onthe particular clinical picture of the disease. Compounds of formula Ican in this case be administered on their own or together withpharmaceutical excipients, namely both in veterinary and in humanmedicine.

[0216] The person skilled in the art is familiar on the basis of his/herexpert knowledge with excipients which are suitable for the desiredpharmaceutical formulation. In addition to solvents, gel formers,suppository bases, tablet excipients, and other active compoundcarriers, it is possible to use, for example, antioxidants, dispersants,emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers,or colorants.

[0217] For an oral administration form, the active compounds are mixedwith the additives suitable therefor, such as vehicles, stabilizers, orinert diluents, and brought by the customary methods into the suitableadministration forms, such as tablets, coated tablets, hard gelatincapsules, aqueous, alcoholic, or oily solutions. Inert excipients whichcan be used are, for example, gum arabic, magnesia, magnesium carbonate,potassium phosphate, lactose, glucose, or starch, in particular,cornstarch. In this case, preparation can be carried out both as dry andmoist granules. Suitable oily vehicles or solvents are, for example,vegetable or animal oils, such as sunflower oil or cod liver oil.

[0218] For subcutaneous or intravenous administration, the activecompounds used, if desired with the substances customary therefor, suchas solubilizers, emulsifiers, or further excipients, are brought intosolution, suspension, or emulsion. Possible solvents are, for example,water, physiological saline solution, or alcohols (e.g., ethanol,propanol, and glycerol). In addition, other possible solvents are sugarsolutions such as glucose or mannitol solutions, or alternatively amixture of the various solvents mentioned.

[0219] Pharmaceutical formulations which are suitable for administrationin the form of aerosols or sprays are, for example, solutions,suspensions, or emulsions of the active compound of formula I in apharmaceutically acceptable solvent, such as, ethanol or water, or amixture of such solvents.

[0220] If required, the formulation can also contain otherpharmaceutical excipients such as surfactants, emulsifiers, andstabilizers, and a propellant. Such a preparation customarily containsthe active compound in a concentration of approximately 0.1 to 10%,typically, of approximately 0.3 to 3%, by weight.

[0221] As used here, treatment includes therapy for a particulardisease, such as treating diseases which are influenced by inhibition ofthe Na⁺/H⁺ exchanger. In this respect, treatment can mean successfullyeliminating the disease, reducing the effects associated with it, and/orreducing its severity. Treatment also includes prevention or prophylaxisof the onset of a disease by treating patients falling into a risk groupor category for developing a particular disease or by treating patientsafter a successful treatment to prevent reoccurrence of the treateddisease. Those skilled in the art can routinely identify patients likelyto present with a disease, thereby qualifying as candidates forprevention therapy, because of factors such as diet, habits (e.g.,smoking), family history for the disease, etc.

[0222] The dose of the active compound of formula I to be administeredand the frequency of administration depend on the potency and durationof action of the compounds used; moreover, also on the nature andseverity of the illness to be treated and on the sex, age, weight, andindividual responsiveness of the mammal to be treated.

[0223] On average, the daily dose of a compound of formula I in the caseof a patient weighing approximately 75 kg is at least 0.001 mg/kg,typically 0.01 mg/kg, to at most 10 mg/kg, usually 1 mg/kg, of bodyweight. In the case of acute episodes of the disease, for example,immediately after suffering a cardiac infarct, even higher andespecially more frequent doses may also be necessary, e.g., up to 4individual doses per day. In particular, in the case of i.v.administration, for example, in the case of an infarct patient in theintensive care unit, up to 200 mg per day may be necessary.

EXPERIMENTAL DESCRIPTIONS AND EXAMPLES

[0224] List of Abbreviations Used: R_(t) Retention time TFATrifluoroacetic acid LCMS Liquid chromatography-mass spectroscopy MSMass spectroscopy CI Chemical Ionization RT Room temperature THFTetrahydrofuran EA Ethyl Acetate

[0225] General:

[0226] The retention times (R_(t)) indicated below relate to LCMSmeasurements having the following parameters: stationary phase: MerckPurospher 3μ2 × 55 mm mobile phase: 95% H₂O (0.05% TFA)→ 95%acetonitrile; 4 min; 95% acetonitrile; 1.5 min → 5% acetonitrile; 1 min;0.5 ml/min

Example 1

[0227] (1H-Benzimidazol-2-yl)-(2,6-dichlorophenyl)amine Hydrochloride

[0228] (1H-Benzimidazol-2-yl)-(2,6-dichlorophenyl)amine was preparedaccording to methods known from the literature (J. Med. Chem., 18, 90(1975)). Recrystallization from hot, dilute hydrochloric acid yieldedthe corresponding hydrochloride as a colorless solid.

[0229] LCMS-R_(t)=3.605 min; MS-Cl: 278.2, 280.0

Example 2

[0230] 2-(2,6-Dichlorophenylamino)-1H-benzimidazol-4-ol Hydrochloride

[0231] Intermediate 1: 1-(2-Amino-6hydroxyphenyl)-3-(2,6-dichlorophenyl)thiourea

[0232] 1.0 equivalent of 2,6-dichlorophenyl isothiocyanate was treatedwith 1.0 equivalent of 2,3-diaminophenol and heated to reflux for 1 h.After cooling to RT, the precipitate was filtered off with suction,washed with ether, and dried. The desired thiourea was obtained in ayield of 61%. M.p.: 202-204° C.

[0233] 2-(2,6-Dichlorophenylamino)-1H-benzimidazol-4-ol hydrochloride

[0234] Intermediate 1 was dissolved in ethanol and treated with 8equivalents of methyl iodide. The mixture was heated to reflux for 8 h.After it cooled to RT, the reaction solution was filtered throughactivated carbon and the filtrate was concentrated in vacuo. The residuewas treated with 0.5 N HCl and the precipitate was filtered off withsuction after 30 min. The residue was stirred once more with EA anddried. The title compound was isolated in a yield of 47%. M.p.: 333-335°C.

[0235] MS(Cl+): 294.1; 296.1

Example 3

[0236] (1H-Benzimidazol-2-yl)-(2,6-dimethylphenyl)amine Trifluoracetate

[0237] 2,6-Dimethylaniline (0.5 g) and 2-chlorobenzimidazole (0.63 g)were mixed in a flask and then kept at 200° C. for 2 h. After cooling,the residue was dissolved out of the flask with 1 N HCl at boiling heat.The material dissolved out was then stirred at RT for 30 min, then theinsoluble material was filtered off with suction and the filtrate wasevaporated. The residue was purified by means of preparative HPLC onRP-18 using acetonitrile/water (0.05% TFA). The clean fractions werecombined, concentrated, and then recrystallized from acetonitrile/water.500 mg of white crystals were obtained.

[0238] LCMS-R_(t): 3.30 min; MS (ES+, M+H⁺): 238.1

Example 4

[0239] (1H-Benzimidazol-2-yl)-(2-chloro-6-methylphenyl)amineHydrochloride

[0240] 2-Chloro-6-methylaniline (0.46 g) and 2-chlorobenzimidazole (0.5g) were mixed in a flask and then kept at 170° C. for 30 min. Aftercooling, the residue was dissolved out of the flask with 1 N HCl and 10%ethanol at boiling heat. The material dissolved out was then stirred atRT for 30 min, then the insoluble material was filtered off with suctionand the filtrate was evaporated. The residue was purified by means ofpreparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). Theclean fractions were combined, the acetonitrile was stripped off, theresidue was adjusted to pH 10 with potassium carbonate solution,extracted three times with EA, and then the combined phases were dried,filtered, and concentrated. The residue was taken up using HCl/water andfreeze-dried. 227 mg of the title compound were obtained.

[0241] LCMS-R_(t): 3.71 min; MS (ES+, M+H⁺): 258.0

Example 5

[0242] (2,6-Dichlorophenyl)-(5,6-difluoro-1H-benzimidazol-2-yl)aminehydrochloride

[0243] 2,6-Dichlorophenyl isothiocyanate (0.3 g) and4,5-difluoro-1,2-phenylenediamine (0.21 g) were stirred at RT for 4 h inTHF (15 ml) and then concentrated and dried in a high vacuum. The foamyresidue was dissolved in ethanol and heated to 70° C. with stirring.Methyl iodide (0.73 ml) was then added dropwise. After three hours, theheating was stopped and the batch was allowed to stand overnight. Afterconcentration, it was taken up using water and EA, and the EA phase wasseparated off, dried with magnesium sulfate, filtered, and concentrated.The residue was purified by means of preparative HPLC on RP-18 usingacetonitrile/water (0.05% TFA). The clean fractions were combined, theacetonitrile was stripped off, the residue was adjusted to pH 10 withpotassium carbonate solution, extracted three times with EA, and thenthe combined phases were dried, filtered, and concentrated. The residuewas taken up using 2 N HCl and freeze-dried. 55 mg of the title compoundwere obtained.

[0244] LCMS-R_(t): 3.83 min; MS (Cl+, M+H⁺): 314.1

Example 6

[0245] (2,6-Dichlorophenyl)-(4-methyl-1H-benzimidazol-2-yl)amineTrifluoracetate

[0246] 2,6-Dichlorophenyl isothiocyanate (0.15 g) and 2,3-diaminotoluene(0.09 g) were dissolved in THF (15 ml), the solution was stirred at RTfor 4 h and then treated with N,N′-dicyclohexylcarbodiimide (0.23 g),and the mixture was boiled under reflux for 6 h. After allowing to standovernight, the reaction mixture was concentrated, treated withacetonitrile/water (80:20), the undissolved material was filtered off,and the solution was purified by means of preparative HPLC on RP-18using acetonitrile/water (0.05% TFA). The product-containing fractionswere combined and brought to dryness. Crystallization fromEA/ether/heptane yielded 85 mg of the title compound.

[0247] LCMS-R_(T): 3.81 min; MS (ES+, M+H⁺): 292.0

Example 7

[0248] (1H-Benzimidazol-2-yl)-(2-chloro-6-fluorophenyl)aminehydrochloride

[0249] 2-Chloro-6-fluoroaniline (0.48 g) and 2-chlorobenzimidazole (0.5g) were mixed in a flask and then kept at 170° C. for 30 min. Aftercooling, the residue was dissolved out of the flask at boiling heatusing 1 N HCl and 10% ethanol. The material dissolved out was thenstirred at RT for 30 min, then the insoluble material was filtered offwith suction and the filtrate was evaporated. The residue was purifiedby means of preparative HPLC on RP-18 using acetonitrile/water (0.05%TFA). The clean fractions were combined, the acetonitrile was strippedoff, the residue was adjusted to pH 10 with potassium carbonatesolution, extracted three times with EA, and then the combined phaseswere dried, filtered, and concentrated. The residue was taken up usingHCl/water and freeze-dried. 27 mg of the title compound were obtained.

[0250] LCMS-R_(t): 3.45 min; MS (ES+, M+H⁺): 262.0

Example 8

[0251] (1H-Benzimidazol-2-yl)-(2,6-dibromophenyl)amine trifluoroacetate

[0252] 2,6-Dibromaniline (0.5 g) was dissolved in absolute dioxane (5ml), trimethylsilyl chloride (0.22 g) was added dropwise through aseptum, and the mixture was then stirred at RT for 2 h.2-Chlorobenzimidazole (0.3 g) dissolved in dioxane was then added andthe mixture was boiled under reflux. After 4 h, it was cooled, thedioxane was stripped off, and the residue was heated at 190° C. for 10min. After cooling, the residue was dissolved out of the flask using 1 NHCl at boiling heat. The insoluble material was then filtered off andthe filtrate was evaporated. The residue was purified by means ofpreparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). Theclean fractions were combined and freeze-dried. 2.4 mg of the titlecompound were obtained.

[0253] LCMS-R_(t): 3.74 min; MS (ES+, M+H⁺): 369.2

Example 9

[0254]2-(2,6-Dichlorophenylamino)-5-fluorobenzimidazole Hydrochloride

[0255] a) 1-(2-Amino-5-fluorophenyl)-3-(2,6-dichlorophenyl)thiourea

[0256] A mixture of 4.37 g (0.0346 mol) of 4-fluoro-1,2-diaminobenzeneand 7.07 g (0.0346 mol) of 2,6-dichlorophenyl isothiocyanate in 150 mlof EA was boiled under reflux for 3 hours. After distilling off thesolvent, the residue was dissolved in methanol, treated with activatedcarbon, ⅔ of the solvent volume was distilled off, and the thiourea wasallowed to crystallize in an ice bath for a number of hours. 8.9 g ofthe desired product was obtained. Colorless crystals,1 st m.p.: 175-178°C.; 2nd m.p.: 294-296° C.

[0257] MS (ES+, M+H⁺): 329.9

[0258] b) 2-(2,6-Dichlorophenylamino)-5-fluorobenzimidazoleHydrochloride

[0259] 1-(2-Amino-5-fluorophenyl)-3-(2,6-dichlorophenyl)-thiourea wasdissolved in ethanol and treated with 8 equivalents of methyl iodide.The mixture was heated to reflux for 6 h. The solvent was distilled off,the residue was treated with water, then the mixture was rendered weaklyalkaline by addition of saturated aqueous sodium hydrogencarbonatesolution, and extracted. After distilling off the solvent, the residuewas purified by column chromatography on silica gel using a mixture ofmethylene chloride and methanol (10:1). After distilling off the solventunder reduced pressure, the residue was dissolved using EA, and thesolution was treated with excess ethereal hydrochloric acid. The mixturewas stirred at RT for approximately 30 minutes, and the crystallinesubstance was filtered off and recrystallized from a mixture of EA andethanol. Colorless crystalline product, m.p.: 294-296° C.

[0260] MS (Cl+, M+H⁺): 296

Example 10

[0261] 2-(2,6-Dichlorophenylamino)-4-fluorobenzimidazole Hydrochloride

[0262] a) 3-Fluoro-2-nitro-phenylhydrazine

[0263] A mixture of 0.01 M 2,6-difluoronitrobenzene and 0.01 M hydrazinehydrate (99% strength) in 30 ml of THF was stirred overnight at RT(exothermic reaction) and the residue was brought to crystallizationafter distilling off the solvent by treating with diisopropyl ether.Crystalline substance, m.p.: 93-95° C.

[0264] MS (Cl+, M+H⁺): 172.1

[0265] b) 2,3-Diaminofluorobenzene was obtained by hydrogenation of0.0038 mol of 3-fluoro-2-nitrophenylhydrazine in 50 ml of methanol usingpalladium on carbon (10% strength) as a catalyst until the absorption ofhydrogen ended. After filtration, 2,3-diaminofluorobenzene was obtainedas a yellow oily substance.

[0266] MS (Cl+, M+H⁺): 127.2

[0267] c) 1-(2-Amino-6-fluorophenyl)-3-(2,6-dichlorophenyl)thiourea wasobtained by reaction of 0.011 M 2,3-diaminofluorobenzene with 0.011 M2,6-dichlorophenyl isothiocyanate in 30 ml of anhydrous THF at RT. Afterdistilling off the solvent, the thiourea was brought to crystallizationunder EA. Crystalline solid, m.p.: 315° C.

[0268] MS (Cl+, M+H⁺): 330.1

[0269] d) 2-(2,6-Dichlorophenylamino)-4-fluorobenzimidazolehydrochloride was obtained analogously to the procedure described inexample 9 by reaction of1-(2-amino-6-fluorophenyl)-3-(2,6-dichlorophenyl)thiourea with 8equivalents of methyl iodide in ethanol. Colorless crystalline solidhaving a wide melting point range of 268-296° C. with foaming.

[0270] MS (Cl+, M+H⁺): 296.1

Example 11

[0271] 2-(2-Trifluoromethyl-6-chlorophenylamino)benzimidazoleHydrochloride

[0272] a) 1-(2-Aminophenyl)-3-(6-chloro-2-trifluoromethylphenyl)urea wasobtained by reaction of equivalent amounts of 1,2-diaminobenzene and2-trifluoromethyl-6-chlorophenyl isocyanate in anhydrous THF, thedesired urea derivative crystallizing out after a short time. Themixture was stirred at RT for approximately 20 hours and the crystallineprecipitate was filtered off. Decomposition point 310° C.

[0273] MS (E+, M+H⁺): 330.1

[0274] b) 2-(2-Trifluoromethyl-6-chlorophenylamino)benzimidazolehydrochloride

[0275] 0.8 g of1-(2-aminophenyl)-3-(6-chloro-2-trifluoromethylphenyl)urea was heatedunder reflux conditions for 5 hours in 10 ml of POCl₃, a clear solutionresulting. After distilling off the phosphorus oxychloride under reducedpressure, the oily residue was treated with water, slow crystallizationtaking place. The crystals were filtered off and chromatographed onsilica gel using a mixture of 10 parts of dichloromethane and 1 part ofmethanol. After distilling off the solvent, the residue was dissolved inEA and rendered strongly acidic using a saturated solution of hydrogenchloride gas in diethyl ether. The crystalline precipitate was filteredoff. Colorless to slightly yellowish crystals. M.p.: 255-288° C.

[0276] MS (Cl+, M+H⁺): 312.2

Example 12

[0277] 2-(2,6-Dichlorophenylamino)-4,5-difluorobenzimidazoleHydrochloride

[0278] a) 1-(2-Amino-5,6-difluorophenyl)-3-(2,6-dichlorophenyl)thioureawas obtained by boiling a mixture of 0.01 M1,2-diamino-3,4-difluorobenzene with 0.01 M 2,6-dichlorophenylisothiocyanate in 50 ml of EA for 4 hours. After distilling off thesolvent, the thiourea was brought to crystallization under diisopropylether. Crystalline solid. M.p.: >310° C.

[0279] MS (Cl+, M+H⁺): 348.0

[0280] b) 2-(2,6-Dichlorophenylamino)-4,5-difluorobenzimidazolehydrochloride was obtained analogously to the procedure described inexample 9b from 3.2 g of1-(2-amino-5,6-difluorophenyl)-3-(2,6-dichlorophenyl)thiourea and 10.6 gof methyl iodide. Crystalline solid, m.p.: 228-230° C.

[0281] MS (Cl+, M+H⁺): 314.0

Example 13

[0282] 2-(2,6-Dichlorophenylamino)-5-hydroxybenzimidazole Hydrobromide

[0283] a) 1-(2-Amino-5-methoxyphenyl)-3-(2,6-dichlorophenyl)thiourea wasobtained analogously to the procedure described in example 12a from0.005 M 1,2-diamino-4-methoxybenzene and 0.005 M 2,6-dichlorophenylisothiocyanate. Crystalline solid. M.p.: 164-166° C. and freshcrystallization; decomposition point: 200° C.

[0284] MS (ES+, M+): 342.0

[0285] b) 2-(2,6-Dichlorophenylamino)-5-methoxybenzimidazolehydrochloride was obtained analogously to the procedure described inexample 9 by reaction of 0.0025 M1-(2-amino-5-methoxyphenyl)-3-(2,6-dichlorophenyl)thiourea with 0.0205 Mmethyl iodide in 20 ml of ethanol. After distilling off the solvent, theresidue was dissolved in a little EA, the solution was rendered stronglyacidic using a saturated solution of hydrogen chloride gas in diethylether, and the crystals were filtered off after a few hours. M.p.:172-174° C.

[0286] MS (Cl+, M+H⁺): 308.0

[0287] c) 2-(2,6-Dichlorophenylamino)-5-hydroxybenzimidazolesydrobromide

[0288] A mixture of 0.05 g of2-(2,6-dichlorophenylamino)-5-methoxybenzimidazole hydrochloride, 0.5 mlof glacial acetic acid, and 0.5 ml of hydrobromic acid (48% strength)was boiled under reflux for 3 hours and the solvent was then distilledoff. The solid residue was brought to crystallization under a little EA.0.02 g of 2-(2,6-dichlorophenylamino)-5-hydroxybenzimidazolehydrobromide was obtained of melting point 265-269° C.

[0289] MS (Cl+, M+H⁺): 294.1

Example 14

[0290] 2-(2,6-Dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazolehydrochloride

[0291] a)1-(2-Amino-3,4,5,6-tetrafluorophenyl)-3-(2,6-dichlorophenyl)thiourea wasobtained by boiling a mixture of 1 g of1,2-diamino-3,4,5,6-tetrafluorobenzene with 1.13 g of 2,6-dichlorophenylisothiocyanate in 30 ml of anhydrous THF for 4 hours.

[0292] After distilling off the solvent, the thiourea was brought tocrystallization under diisopropyl ether and 1.88 g of1-(2-amino-3,4,5,6-tetrafluorophenyl)-3-(2,6-dichlorophenyl)thioureawere obtained as a crystalline solid. M.p.: >300° C.

[0293] MS (ES+, M+H⁺): 384.06

[0294] b) 2-(2,6-Dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazolehydrochloride was obtained analogously to the procedure described inexample 9b from 1.5 g of1-(2-amino-3,4,5,6-tetrafluorophenyl)-3-(2,6-dichlorophenyl)thiourea and4.4 g of methyl iodide and subsequent column chromatography on silicagel using a mixture of 10 parts of EA, 5 parts of n-heptane, 5 parts ofdichloromethane, 5 parts of methanol, and 1 part of aqueous concentratedammonia. Crystalline solid, m.p.: 220-222° C.

[0295] MS (Cl+, M+H⁺): 350.2

Example 15

[0296] 2-(2,6-Dichlorophenylamino)-4,6-difluorobenzimidazoleHydrochloride

[0297] a) 1,2-Diamino-3,5-difluorobenzene was obtained by hydrogenationof 5 g of 2-amino-3,5-difluoronitrobenzene with 0.8 g of palladiumcatalyst on carbon at RT and normal pressure. After distilling off thesolvent, a dark partially crystalline oil was obtained, which was usedwithout further purification for the preparation of stage b.

[0298] b) 1-(2-Amino-4,6-difluorophenyl)-3-(2,6-dichlorophenyl)thioureawas obtained by allowing a mixture of 0.01 M1,2-diamino-3,5-difluorobenzene with 0.01 M 2,6-dichlorophenylisothiocyanate in 60 ml of anhydrous THF to stand over the weekend atRT. After distilling off the solvent, the thiourea was brought tocrystallization under diisopropyl ether. Crystalline solid, m.p.:310-314° C.

[0299] MS (Cl+, M+H⁺): 348.1

[0300] c) 2-(2,6-Dichlorophenylamino)-4,5-difluorobenzimidazolehydrochloride was obtained analogously to the procedure described inexample 9b from 2 g of1-(2-amino-4,6-difluorophenyl)-3-(2,6-dichlorophenyl)thiourea and 6.4 gof methyl iodide. Crystalline solid, m.p.: 232-234° C.

[0301] MS (Cl+, M+H⁺): 314.2

Example 16

[0302] (1H-Benzimidazol-2-yl)-(2-chlorophenyl)amine trifluoroacetate

[0303] 2-Chloraniline (0.5 g) and 2-chlorobenzimidazole (0.6 g) weremixed in a flask and then kept at 225° C. for 2 h. After cooling, theresidue was dissolved out of the flask at boiling heat using 1 N HCl,the insoluble material was filtered off with suction, and the filtratewas adjusted to pH 9-10 using potassium carbonate and concentrated. Theresidue was treated with hot methanol, the insoluble material wasfiltered off, the mother liquor was treated with ether, and theprecipitate was filtered off again. The mother liquor was concentratedand the residue was crystallized again from methanol/ether. Afterfiltering off the crystals with suction, the mother liquor wasconcentrated and the residue was purified by means of preparative HPLCon RP-18 using acetonitrile/water (0.05% TFA). The clean fractions werecombined and freeze-dried. 100 mg of the title compound were obtained.

[0304] LCMS-R_(t): 3.16 min; MS (Cl+, M+H⁺): 244.0

Example 17

[0305] (1H-Benzimidazol-2-yl)-(2-trifluoromethylphenyl)amineTrifluoroacetate

[0306] 2-Aminobenzotrifluoride (0.5 g) and 2-chlorobenzimidazole (0.47g) were mixed in a flask and then kept at 225° C. for 2 h. Aftercooling, the residue was dissolved out of the flask at boiling heatusing 1 N HCl and the insoluble matter was filtered off with suctionafter cooling. The filtrate was concentrated and the residue waspurified by means of preparative HPLC on RP-18 using acetonitrile/water(0.05% TFA). The clean fractions were combined and freeze-dried. 52 mgof the title compound were obtained.

[0307] LCMS-R_(t): 3.65 min; MS (Cl+, M+H⁺): 278.1

Example 18

[0308] (1H-Benzimidazol-2-yl)-(2-bromophenyl)amine Trifluoroacetate

[0309] 2-Bromoaniline (0.5 g) and 2-chlorobenzimidazole (0.44 g) werereacted according to example 17. 117 mg of the title compound wereobtained.

[0310] LCMS-R_(t): 3.55 min; MS (ES+, M+H⁺): 288.0

Example 19

[0311] (1H-Benzimidazol-2-yl)-o-tolylamine aydrochloride

[0312] 2-Methylaniline (0.5 g) and 2-chlorobenzimidazole (0.71 g) weremixed in a flask and then kept at 250° C. for 2 h. After cooling, theresidue was dissolved out of the flask at boiling heat using 1 N HCl,the insoluble material was filtered off with suction, and the filtratewas evaporated. The residue was purified by means of preparative HPLC onRP-18 using acetonitrile/water (0.05% TFA). The clean fractions werecombined, the acetonitrile was stripped off, the residue was renderedalkaline using potassium carbonate solution, extracted three times withEA, and the combined phases were then dried, filtered, and concentrated.The residue was taken up using 2 N HCl and the solution wasfreeze-dried. 110 mg of the title compound were obtained.

[0313] LCMS-R_(t): 3.54 min; MS (Cl+, M+H⁺): 224.1

[0314] Pharmacological Data:

[0315] Test Description:

[0316] In this test, the recovery of the intracellular pH (pH_(i)) afteran acidification was determined which commences with functional NHE evenunder bicarbonate-free conditions. For this, the pH_(i) was determinedusing the pH-sensitive fluorescent dye BCECF (Calbiochem, the precursorBCECF-AM was employed). The cells were first loaded with BCECF. TheBCECF fluorescence was determined in a “Ratio Fluorescence Spectrometer”(Photon Technology International, South Brunswick, N.J., USA) atexcitation wavelengths of 505 and 440 nm and an emission wavelength of535 nm and converted into the pH_(i) by means of calibration curves. Thecells were incubated in NH₄Cl buffer (pH 7.4) even in the case of BCECFloading (NH₄Cl buffer: 115 mM NaCl, 20 mM NH₄Cl, 5 mM KCl, 1 mM CaCl₂, 1mM MgSO₄, 20 mM Hepes, 5 mM glucose, 1 mg/ml of BSA; a pH of 7.4 is setusing 1 M NaOH). The intracellular acidification was induced by additionof 975 μl of an NH₄Cl-free buffer (see below) to 25 μl aliquots of thecells incubated in NH₄Cl buffer. The subsequent rate of pH recovery wasrecorded for two minutes in the case of NHE1, for five minutes in thecase of NHE2, and for three minutes in the case of NHE3. For thecalculation of the inhibitory potency of the substances tested, thecells were first investigated in buffers in which a complete pH recoveryor no pH recovery at all took place. For the complete pH recovery(100%), the cells were incubated in Na+-containing buffer (133.8 mMNaCl, 4.7 mM KCl, 1.25 mM CaCl₂, 1.25 mM MgCl₂, 0.97 mM Na₂HPO₄, 0.23 mMNa₂HPO₄, 5 mM Hepes, 5 mM glucose; a pH of 7.0 is set using 1 M NaOH).For the determination of the 0% value, the cells were incubated in anNa+-free buffer (133.8 mM choline chloride, 4.7 mM KCl, 1.25 mM CaCl₂,1.25 mM MgCl₂, 0.97 mM K₂HPO₄, 0.23 mM KH₂PO₄, 5 mM Hepes, 5 mM glucose;a pH of 7.0 is set using 1 M NaOH). The substances to be tested wereapplied in the Na+-containing buffer. The recovery of the intracellularpH at each tested concentration of a substance was expressed in percentof the maximum recovery. The IC value of the respective substance forthe individual NHE subtypes was calculated from the percentage values ofthe pH recovery by means of the program Sigma-Plot.

[0317] Results: IC₅₀ [μM], Example (rNHE3) 1 0.53 2 0.47 3 0.64 4 0.49 50.78 6 0.39 7 0.52 8 0.65 9 1.0 10 3.2 11 0.83 12 2.9 13 1.1 14 5.6 151.6 16 0.63 17 3.5 18 1.2 19 3.5

What is claimed is:
 1. A substituted benzimidazole of formula I

in which: R1 and R5 are, independently of one another, F, Cl, Br, I, CN,alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted orpartially or completely substituted by fluorine; or R1 and R5 arecycloalkyl having 3 to 7 carbon atoms, which is unsubstituted orpartially or completely substituted by fluorine; or R1 and R5 are,independently of one another, OH or O-alkyl having 1 to 4 carbon atoms,in which alkyl is unsubstituted or partially or completely substitutedby fluorine; or R1 and R5 are, independently of one another, OCOR10,NR11R12, COR13, COOH, COOR14, CONR11R12, or —(O)_(n)—SO_(m)R15, in whichn is 0 or 1 and m is 0, 1, or 2; or R1 and R5 are O-phenyl, in whichphenyl is unsubstituted or substituted by one to three substituentsselected, independently of one another, from F, Cl, Br, I, alkyl having1 to 4 carbon atoms, OH, O-alkyl having 1 to 4 carbon atoms, NR16R17,CN, or (C₁-C₄)-alkylsulfonyl, in which alkyl is unsubstituted orpartially or completely substituted by fluorine; R16 and R17 are,independently of one another, H or alkyl having 1 to 4 carbon atoms, inwhich alkyl is unsubstituted or partially or completely substituted byfluorine; R10 is H or alkyl having 1 to 4 carbon atoms, in which alkylis unsubstituted or partially or completely substituted by fluorine; R11and R12 are, independently of one another, H, alkyl having 1 to 4 carbonatoms, which is unsubstituted or partially or completely substituted byfluorine, and at least one CH₂ group of said alkyl is optionallyreplaced by O or NR18; or R11 and R12, together with the nitrogen atomto which they are bonded, form a 5-, 6-, or 7-membered ring; or R11 andR12 are, independently of one another, COR19 or SO₂R20; R18, R19, andR20 are, independently of one another, H or alkyl having 1 to 4 carbonatoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine; R13 and R14 are alkyl having 1 to 4 carbonatoms, which is unsubstituted or partially or completely substituted byfluorine; R15 is alkyl or O-alkyl, in which the alkyl groups have 1 to 4carbon atoms and are unsubstituted or partially or completelysubstituted by fluorine; or R15 is OH or NR21R22; R21 and R22 are,independently of one another, H or alkyl having 1 to 4 carbon atoms, inwhich alkyl is unsubstituted or partially or completely substituted byfluorine, and at least one CH₂ group of said alkyl is optionallyreplaced by O or NR23; R23 is H or alkyl having 1 to 4 carbon atoms, inwhich alkyl is unsubstituted or partially or completely substituted byfluorine; or R21 and R22, together with the nitrogen atom to which theyare bonded, form a 5-, 6-, or 7-membered ring; but R1 and R5 cannotsimultaneously be Cl or CH₃; R2, R3, and R4 are H or one of the radicalsR2, R3, or R4 is optionally F; R6, R7, R8, and R9 are, independently ofone another, H, F, Cl, Br, I, CN, alkyl, or O-alkyl, in which the alkylgroups have 1 to 4 carbon atoms and are unsubstituted or partially orcompletely substituted by fluorine; or R6, R7, R8, and R9 are cycloalkylhaving 3 to 7 carbon atoms, which is unsubstituted or partially orcompletely substituted by fluorine; or R6, R7, R8, and R9 are,independently of one another, OH, OCOR24, or NR25R26; R24 is H or alkylhaving 1 to 4 carbon atoms, in which alkyl is unsubstituted or partiallyor completely substituted by fluorine; R25 and R26 are, independently ofone another, H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine; or R25and R26 are COR27; or R25 and R26, together with the nitrogen atom towhich they are bonded, form a 5-, 6-, or 7-membered ring, and at leastone CH₂ group thereof is optionally replaced by O or NR18; R27 is H oralkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted orpartially or completely substituted by fluorine; or a pharmaceuticallytolerable salt or trifluoroacetate thereof.
 2. A compound of claim 1, inwhich: R1 and R5 are, independently of one another, F, Cl, Br, CN, alkylhaving 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, cycloalkyl having 3 to7 carbon atoms, O-alkyl having 1 to 4 carbon atoms, OH, OCF₃, OCH₂CF₃,OCF₂CF₃, OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, —O_(m)—SO₂R15,or O-phenyl; m is 0 or 1; R10 is H, alkyl having 1 to 4 carbon atoms,CF₃, CH₂CF₃, or CF₂CF₃; R11 and R12 are, independently of one another,H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, and at leastone CH₂ group of said alkyl is optionally replaced by O or NR18; or R11and R12, together with the nitrogen atom to which they are bonded, forma 5-, 6-, or7-membered ring; or R11 and R12 are, independently of oneanother, COR19 or SO₂R20; R18, R19, and R20 are, independently of oneanother, H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;R13 and R14 are, independently of one another, alkyl having 1 to 4carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃; R15 is alkyl having 1 to 4 carbonatoms, CF₃, CH₂CF₃, CF₂CF₃, OH, O-alkyl having 1 to 4 carbon atoms,OCF₃, OCH₂CF₃, OCF₂CF₃, or NR21R22; R21 and R22 are, independently ofone another, H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, orCF₂CF₃; or R21 and R22, together with the nitrogen atom to which theyare bonded, are —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₂—O—(CH₂)₂—, or—(CH₂)₂—N—R30-(CH₂)₂; R30 is H, CH₃, or CF₃; but R1 and R5 cannotsimultaneously be Cl or CH₃; R2, R3, and R4 are H or one of the radicalsR2, R3, or R4 is optionally F; R6, R7, R8, and R9 are, independently ofone another, H, F, Cl, Br, I, CN, alkyl having 1 to 4 carbon atoms, CF₃,CH₂CF₃, CF₂CF₃, cycloalkyl having 3 to 7 carbon atoms, OH, O-alkylhaving 1 to 4 carbon atoms, OCF₃, OCH₂CF₃, OCF₂CF₃, OCOR24, or NR25R26;R24 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃; R25and R26 are, independently of one another, H, alkyl having 1 to 4 carbonatoms, CF₃, CH₂CF₃, CF₂CF₃, or COR27; or R25 and R26, together with thenitrogen atom to which they are bonded, form a 5-, 6-, or 7-memberedring; R27 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, orCF₂CF₃.
 3. A compound of claim 1, in which: R1 and R5 are, independentlyof one another, F, Cl, Br, CN, methyl, ethyl, isopropyl, CF₃,cyclopropyl, OH, O-methyl, O-ethyl, O-isopropyl, OCF₃, O-acetyl, NH₂,N(CH₃)₂, N(CH₂CH₃)₂, N-pyrrolidino, N-piperidino, N-morpholino,N-(N′-methyl)-piperazino, NHSO₂Me, acetyl, COOH, COOR14, CONR11R12,SO₂R15, or O-phenyl; R11 and R12 are, independently of one another, H,methyl, or ethyl; R14 is methyl or ethyl; R15 is CH₃, CF₃, OH, OCH₃,OCF₃, or NR21 R22; R21 and R22 are, independently of one another, H ormethyl; but R1 and R5 cannot simultaneously be Cl or CH₃; R2, R3, and R4are H; R6, R7, R8, and R9 are, independently of one another, are H, F,Cl, CN, CH₃, C₂H₅, isopropyl, CF₃, cyclopropyl, OH, OCH₃, OCF₃,O-acetyl, or NR25R26; R25 and R26 are, independently of one another, H,methyl, or acetyl.
 4. A compound of claim 1 in which: R1 and R5 are,independently of one another, F, Cl, Br, CN, methyl, ethyl, isopropyl,CF₃, cyclopropyl, OH, O-methyl, O-ethyl, O-isopropyl, OCF₃, O-acetyl,NH₂, N(CH₃)₂, N(CH₂CH₃)₂, N-pyrrolidino, N-piperidino, N-morpholino,N-(N′-methyl)-piperazino, NHSO₂Me, acetyl, COOH, COOR14, CONR11R12,SO₂R15, or O-phenyl; R11 and R12 are, independently of one another, H,methyl, or ethyl; R14 is methyl or ethyl; R15 is CH₃, CF₃, OH, OCH₃,OCF₃, or NR21R22; R21 and R22 are, independently of one another, H ormethyl; but R1 and R5 cannot simultaneously be Cl or CH₃; R2, R3, and R4are H; R6 and R9 are, independently of one another, H, F, Cl, CN, CH₃,CF₃, cyclopropyl, OH, OCH₃, OCF₃, O-acetyl, or NR25R26; R25 and R26 are,independently of one another, H, methyl, or acetyl; R7 and R8 are,independently of one another, H, F, or OH.
 5. A compound of claim 1,which is: (1H-benzimidazol-2-yl)-(2,6-dichlorophenyl)amine;2-(2,6-dichlorophenylamino)-1H-benzimidazol-4-ol;(1H-benzimidazol-2-yl)-(2,6-dimethylphenyl)amine;(1H-benzimidazol-2-yl)-(2-chloro-6-methylphenyl)amine;(2,6-dichlorophenyl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine;(2,6-dichlorophenyl)-(4-methyl-1H-benzimidazol-2-yl)amine;(1H-benzimidazol-2-yl)-(2-chloro-6-fluorophenyl)amine;(1H-benzimidazol-2-yl)-(2,6-dibromophenyl)amine;2-(2,6-dichlorophenylamino)-5-fluorobenzimidazole;2-(2,6-dichlorophenylamino)-4-fluorobenzimidazole;2-(2-trifluoromethyl-6-chlorophenylamino)benzimidazole;2-(2,6-dichlorophenylamino)-4,5-difluorobenzimidazole;2-(2,6-dichlorophenylamino)-5 hydroxybenzimidazole;2-(2,6-dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazole;2-(2,6-dichlorophenylamino)-4,6-difluorobenzimidazole;(1H-benzimidazol-2-yl)-(2-chlorophenyl)amine;(1H-benzimidazol-2-yl)-(2-trifluoromethylphenyl)amine;(1H-benzimidazol-2-yl)-(2-bromophenyl)amine; or(1H-benzimidazol-2-yl)-o-tolylamine; or a pharmaceutically tolerablesalt or trifluoroacetate thereof.
 6. A pharmaceutical composition,comprising at least one compound of claim 1 and a pharmaceuticallyacceptable carrier.
 7. A method for treating diseases which areinfluenced by inhibition of the Na⁺/H⁺ exchanger, comprisingadministering to a patient in need thereof an effective amount of atleast one compound of formula I

in which: R1 and R5 are, independently of one another, H, F, Cl, Br, I,CN, alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted orpartially or completely substituted by fluorine; or R1 and R5 arecycloalkyl having 3 to 7 carbon atoms, which is unsubstituted orpartially or completely substituted by fluorine; or R1 and R5 are OH orO-alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted orpartially or completely substituted by fluorine; or R1 and R5 areOCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, or —(O)_(n)—SO_(m)R15,in which n is 0 or 1 and m is 0, 1, or 2; or R1 and R5 are O-phenyl, inwhich phenyl is unsubstituted or substituted by one to threesubstituents selected from F, Cl, Br, I, alkyl having 1 to 4 carbonatoms, OH, O-alkyl having 1 to 4 carbon atoms, NR16R17, CN, or(C₁-C₄)-alkylsulfonyl, in which the alkyl groups are unsubstituted orpartially or completely substituted by fluorine; R16 and R17 are H oralkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted orpartially or completely substituted by fluorine; R10 is H or alkylhaving 1 to 4 carbon atoms, in which alkyl is unsubstituted or partiallyor completely substituted by fluorine; R11 and R12 are, independently ofone another, H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine, and atleast one CH₂ group of said alkyl is optionally replaced be by O orNR18; or R11 and R12, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring; or R11 and R12 are COR19 orSO₂R20; R18, R19, and R20 are, independently of one another, H or alkylhaving 1 to 4 carbon atoms, in which alkyl is unsubstituted or partiallyor completely substituted by fluorine; R13 and R14 are alkyl having 1 to4 carbon atoms, which is unsubstituted or partially or completelysubstituted by fluorine; R15 is alkyl or O-alkyl, in which the alkylgroups have 1 to 4 carbon atoms and are unsubstituted or partially orcompletely substituted by fluorine; or R15 is OH or NR21R22; R21 and R22are, independently of one another, H or alkyl having 1 to 4 carbonatoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine, and at least one CH₂ group of said alkyl isoptionally replaced by O— or NR23; R23 is H or alkyl having 1 to 4carbon atoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine; or R21 and R22, together with the nitrogen atomto which they are bonded, form a 5-, 6-, or 7-membered ring; R2, R3, andR4 are, independently of one another, H or F; R6, R7, R8, and R9 are,independently of one another, H, F, Cl, Br, I, CN, alkyl, or O-alkyl, inwhich the alkyl groups have 1 to 4 carbon atoms and are unsubstituted orpartially or completely substituted by fluorine; or R6, R7, R8, and R9are cycloalkyl having 3 to 7 carbon atoms, which is unsubstituted orpartially or completely substituted by fluorine; or R6, R7, R8, and R9are OH, OCOR24, or NR25R26; R24 is H or alkyl having 1 to 4 carbonatoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine; R25 and R26 are, independently of one another,H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstitutedor partially or completely substituted by fluorine; or R25 and R26 areCOR27; or R25 and R26, together with the nitrogen atom to which they arebonded, form a 5-, 6-, or 7-membered ring, and at least one CH₂ groupthereof is optionally replaced by O or NR18; R27 Is H or alkyl having 1to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine; or a pharmaceutically tolerable saltthereof.
 8. A method for treating disorders of the respiratory drive,comprising administering to a patient in need thereof an effectiveamount of at least one compound of claim
 7. 9. A method for treatingsleep-related respiratory disorders, comprising administering to apatient in need thereof an effective amount of at least one compound ofclaim
 7. 10. The method of claim 9, wherein the sleep-relatedrespiratory disorder is sleep apnea.
 11. A method for treating snoring,comprising administering to a patient in need thereof an effectiveamount of at least one compound of claim
 7. 12. A method for treatingacute and chronic kidney diseases, comprising administering to a patientin need thereof an effective amount of at least one compound of claim 7.13. The method of claim 12, wherein the acute and chronic kidneydiseases are acute kidney failure and chronic kidney failure.
 14. Amethod for treating disorders of intestinal function, comprisingadministering to a patient in need thereof an effective amount of atleast one compound of claim
 7. 15. A method for treating disorders ofbile function, comprising administering to a patient in need thereof aneffective amount of at least one compound of claim
 7. 16. A method fortreating ischemic conditions of the peripheral and central nervoussystem and stroke, comprising administering to a patient in need thereofan effective amount of at least one compound of claim
 7. 17. A methodfor treating ischemic conditions of peripheral organs and limbs,comprising administering to a patient in need thereof an effectiveamount of at least one compound of claim
 7. 18. A method for treatingstates of shock, comprising administering to a patient in need thereofan effective amount of at least one compound of claim
 7. 19. A methodfor treating a patient during surgical operations, comprisingadministering to a patient in need thereof an effective amount of atleast one compound of claim
 7. 20. A method of claim 19, where saidsurgical operations is an organ transplantation.
 21. A method of claim19, wherein said patient is a recipient of an organ transplant.
 22. Amethod of claim 19, wherein said patient is a donor of an organtransplant.
 23. A method for treating an organ transplant, whichcomprises contacting an organ transplant with an effective amount of atleast one compound of claim
 7. 24. A method of claim 23, wherein saidcontacting occurs during storage of said organ transplant.
 25. A methodof claim 23, wherein said contacting occurs during transfer of saidorgan transplant.
 26. A method for treating illnesses in which cellproliferation is a primary or secondary cause, comprising administeringto a patient in need thereof an effective amount of at least onecompound of claim
 7. 27. A method for treating disorders of lipidmetabolism, comprising administering to a patient in need thereof aneffective amount of at least one compound of claim
 7. 28. A method fortreating attack by ectoparasites in human and veterinary medicine,comprising administering to a patient in need thereof an effectiveamount of at least one compound of claim
 7. 29. A method for treating aperson susceptible to at least one disease which is influenced byinhibition of the Na⁺/H⁺ exchanger, comprising administering to apatient in need thereof an effective amount of at least one compound ofclaim 7.